Maximal airway narrowing to inhaled nonsensitizing stimuli is limited to a mild degree in nonasthmatic and mildly asthmatic subjects. We investigated whether this limitation is due to a nonspecific inhibitory mechanism (with regard to the agonist) by comparing the maximal response plateaus of histamine and methacholine dose-response curves. Twenty subjects (15 nonasthmatics, 5 asthmatics) were selected in order to cover a wide distribution of airway responsiveness from the normal into the mildly asthmatic range. The subjects inhaled doubling doses of either histamine (up to 54 mumol) or methacholine (up to 340 mumol), delivered to the mouth during tidal breathing, on 2 separate days. The response was measured from volume-history-standardized, partial expiratory flow-volume curves as the flow at 40% of the control vital capacity (V40p), and expressed as the percentage fall from baseline value. Sixteen subjects demonstrated a plateau for both histamine and methacholine. The maximal response on the plateau was not significantly different between the 2 agonists, nor was there a difference in the provocative dose causing a 40% fall in V40p (PD40). The slope of the dose-response curve was significantly steeper for histamine than for methacholine (p less than 0.001), whereby the histamine plateau was reached at relatively lower doses (p less than 0.01). The maximal response was inversely related to logPD40, and this relationship did not differ between histamine and methacholine. We conclude that maximal airway narrowing in vivo is limited by an inhibitory mechanism that is not dependent on the pharmacodynamic properties of the agonist. The results suggest that the extent of inhibition and the degree of airway responsiveness are determined by related mechanisms.